Yoo, Wonbeak Lee, Jaemin Noh, Kyung Hee Lee, Sangmin Jung, Dana Kabir, Mohammad Humayun Parka, Dongmin Lee, Cheolju Kwon, Ki-Sun Kim, Ji-Su Kim, Seokho 2024-01-19T19:02:31Z 2024-01-19T19:02:31Z 2021-09-05 2019-10-07 2041-4889 https://pubs.kist.re.kr/handle/201004/119463 Progranulin (PGRN) is a cysteine-rich secreted protein expressed in endothelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being implicated in tissue remodeling, development, inflammation, and protein homeostasis. However, these findings are controversial, and the role of PGRN in liver disease remains unknown. In the current study, we examined the effect of PGRN in two different models of chronic liver disease, methionine-choline-deficient diet (MCD)-induced non-alcoholic steatohepatitis (NASH) and carbon tetrachloride (CCl4)-induced liver fibrosis. To induce long-term expression of PGRN, PGRN-expressing adenovirus was delivered via injection into the tibialis anterior. In the CCl4-induced fibrosis model, PGRN showed protective effects against hepatic injury, inflammation, and fibrosis via inhibition of nuclear transcription factor kappa B (NF-kappa B) phosphorylation. PGRN also decreased lipid accumulation and inhibited pro-inflammatory cytokine production and fibrosis in the MCD-induced NASH model. In vitro treatment of primary macrophages and Raw 264.7 cells with conditioned media from hepatocytes pre-treated with PGRN prior to stimulation with tumor necrosis factor (TNE)-alpha or palmitate decreased their expression of pro-inflammatory genes. Furthermore, PGRN suppressed inflammatory and fibrotic gene expression in a cell culture model of hepatocyte injury and primary stellate cell activation. These observations increase our understanding of the role of PGRN in liver injury and suggest PGRN delivery as a potential therapeutic strategy in chronic inflammatory liver disease. English NATURE PUBLISHING GROUP GRANULIN-EPITHELIN PRECURSOR KAPPA-B INSULIN SENSITIVITY THERAPEUTIC TARGET SERUM PROGRANULIN GROWTH-FACTOR EXPRESSION PGRN ACTIVATION PROTECTS Progranulin attenuates liver fibrosis by downregulating the inflammatory response Article 10.1038/s41419-019-1994-2 1 CELL DEATH & DISEASE, v.10 CELL DEATH & DISEASE 10 scie scopus 000489079300004 2-s2.0-85073054765 Cell Biology Cell Biology Article GRANULIN-EPITHELIN PRECURSOR KAPPA-B INSULIN SENSITIVITY THERAPEUTIC TARGET SERUM PROGRANULIN GROWTH-FACTOR EXPRESSION PGRN ACTIVATION PROTECTS